Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

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222

296

The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4ϫ 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

Section: Discussionmentioning

confidence: 99%

4-Methylmethcathinone (Mephedrone): Neuropharmacological Effects of a Designer Stimulant of Abuse

Hadlock¹,

Webb²,

McFadden³

et al. 2011

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296

“…Brain concentrations of METH and its metabolite, AMPH, were measured by liquid chromatography-tandem mass spectrometry as described previously (Truong et al, 2005). The whole brains (except for the striatum) were weighed and homogenized separately in 10 ml water.…”

Section: Methodsmentioning

confidence: 99%

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

Vieira-Brock

McFadden

Nielsen

et al. 2015

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Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus selfadminister nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving a4b2 and a6b2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal a4b2 expression, as assessed using [125 I]epibatidine. Both METH and nicotine decreased striatal a6b2 expression, as assessed using [125 I]aconotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting a4b2 and/or a6b2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

“…Vesicular DA Content. Vesicular DA content was measured by high-performance liquid chromatography as described previously (Sandoval et al, 2003;Truong et al, 2005). The P3 (membraneassociated vesicles) and P4 (cytoplasmic vesicles) pellets were prepared as described above, and they were resuspended in ice-cold tissue buffer at 50 and 100 mg of the original striatal wet weight per milliliter of tissue buffer, respectively.…”

Section: Downloaded Frommentioning

confidence: 99%

“…The DAT assay buffer, pH 7.4, consisted of 126 mM NaCl, 4.8 mM KCl, 1.3 mM CaCl 2 , 16 mM sodium phosphate, 1.4 mM MgSO 4 , and 11 mM dextrose (Sandoval et al, 2001). The tissue buffer, pH 2.5, consisted of 50 mM sodium phosphate, 30 mM citric acid, and 10% (v/v) methanol (Sandoval et al, 2003;Truong et al, 2005). VMAT-2 antibody (AB1767) was purchased from Chemicon International, Na ϩ / K ϩ -ATPase antibody was from BD Biosciences (San Jose, CA), piccolo antibody was from Abcam Inc. (Cambridge, MA), actin antibody was from ICN Biotechnologies (Costa Mesa, CA), and DAT antibody was generously provided by Dr. Roxanne Vaughan (University of North Dakota, Grand Forks, ND).…”

Section: Downloaded Frommentioning

confidence: 99%

Methylphenidate Administration Alters Vesicular Monoamine Transporter-2 Function in Cytoplasmic and Membrane-Associated Vesicles

Volz¹,

Farnsworth²,

King³

et al. 2007

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109

In vivo methylphenidate (MPD) administration increases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity, VMAT-2-mediated dopamine (DA) transport, and DA content in a nonmembrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction purified from rat striatum: a phenomenon attributed to a redistribution of VMAT-2-associated vesicles within nerve terminals. In contrast, the present study elucidated the nature of, and the impact of MPD on, VMAT-2-associated vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles). Results revealed that, in striking contrast to the cytoplasmic vesicles, DA transport velocity versus substrate concentration curves in the membrane-associated vesicles were sigmoidal, suggesting positive cooperativity with respect to DA transport. Additionally, DA transport into membrane-associated vesicles was greater in total capacity in the presence of high DA concentrations than transport into cytoplasmic vesicles. Of potential therapeutic relevance, MPD increased DA transport into the membrane-associated vesicles despite rapidly decreasing (presumably by redistributing) VMAT-2 immunoreactivity in this fraction. Functional relevance was suggested by findings that MPD treatment increased both the DA content of the membrane-associated vesicle fraction and K ϩ -stimulated DA release from striatal suspensions. In summary, the present data demonstrate the existence of a previously uncharacterized pool of membrane-associated VMAT-2-containing vesicles that displays novel transport kinetics, has a large sequestration capacity, and responds to in vivo pharmacological manipulation. These findings provide insight into both the regulation of vesicular DA sequestration and the mechanism of action of MPD, and they may have implications regarding treatment of disorders involving abnormal DA disposition, including Parkinson's disease and substance abuse.Methylphenidate (MPD) is a commonly prescribed psychostimulant used to treat attention-deficit hyperactivity disorder. It is well established that MPD binds with high affinity to the neuronal dopamine transporter (DAT) where it blocks the inward transport of dopamine (DA) (Wayment et al., 1999;. In addition, MPD indirectly affects DA transport by the vesicular monoamine transporter-2 (VMAT-2), a transporter protein that is responsible for the sequestration of cytoplasmic DA. Specifically, MPD administration increases [ 3 H]DA transport into nonmembrane-associated (referred to herein as cytoplasmic) vesicles purified from lysates of striatal synaptosomes prepared from treated rats (Sandoval et al., 2002(Sandoval et al., , 2003. MPD also increases DA content in the cytoplasmic vesicle subcellular fraction (Sandoval et al., 2002). These phenomena probably result from a redistribution of VMAT-2-containing vesicles within nerve terminals away from membranes and into the cytoplasm (Sandoval et al., 2002).Recent attention has focused on the regulation of cytop...